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Post-exposure prophylaxis for HIV infection
Post-exposure prophylaxis (PEP) means taking antiretroviral medicines (ART) after being potentially exposed to HIV to prevent becoming infected. PEP should be used only in emergency situations and must be started within 72 hours after a recent possible exposure to HIV. If you think you’ve recently been exposed to HIV during sex or through sharing needles and works to prepare drugs or if you’ve been sexually assaulted, talk to your health care provider or an emergency room doctor about PEP right away. The current initial PEP regimen of choice is tenofovir disoproxil fumarate + emtricitabine plus either raltegravir or dolutegravir. =History= Zidovudine (AZT) was approved as a treatment for AIDS in 1987. As AIDS patients started seeking treatment in medical centers, it sometimes happened that a healthcare worker would be exposed to HIV during work. Some people thought to try giving health care workers AZT to prevent seroconversion. This practice dramatically decreased the incidence of seroconversion among health workers when done under certain conditions. Later the question arose of whether to give HIV treatment to people who had non-occupational exposure, for example, when a condom breaks while a person with HIV has unprotected sex with an HIV-negative person in a single incidence, or in the case of unprotected sex with an anonymous partner, or in the case of a non-habitual incident of sharing a syringe for injection drug use. Evidence suggests that PEP also reduces the risk of HIV infection in these cases. Since taking HIV-attacking medications shortly after exposure was proven to reduce the risk of contracting HIV, this led to research into pre-exposure prophylaxis, which would mean taking medication before any exposure to HIV in anticipation of being in a situation which was likely to expose one to HIV infection. =Risk evaluation= Risk factor must be considered in order to consider the individual as a candidate for HIV post-exposure prophylaxis. For example, having unprotected sex with HIV positive partner is considered risky, but sharing sex toys, spitting and biting considered to be negligible risk for evaluation of pep. The highest non-sexual risk is involve blood transfusion and the highest among sexual contact involve receptive anal intercoursehttp://www.cdc.gov/hiv/pdf/programresources/cdc-hiv-npep-guidelines.pdf. =Treatment= Antiretroviral Agents for PEP In the case of HIV exposure, post-exposure prophylaxis is a course of antiretroviral drugs which reduces the risk of seroconversion after events with high risk of exposure to HIV (e.g., unprotected anal or vaginal sex, needlestick injuries, or sharing needles). The CDC recommends PEP for any HIV negative person who has recently been exposed to HIV for any reason. To be most effective, treatment should begin within an hour of exposure. After 72 hours post-exposure PEP is much less effective, and may not be effective at all. Prophylactic treatment for HIV typically lasts four weeks. While there is compelling data to suggest that PEP after HIV exposure is effective, there have been cases where it has failed. Failure has often been attributed to the delay in receiving treatment (greater than 72 hours post-exposure), the level of exposure, duration of treatment (lack of adherence to the 28 day regimen), or all three. However, given that—for non-occupational exposures—the time and level of exposure are based on patient-supplied information, absolute data is unavailable. The standard antibody window period begins after the last day of PEP treatment. Doctors will advise patients who received PEP to get an antibody test at 6 months post-exposure as well as the standard 3 month test. The antiretroviral regimen used in PEP is the same as the standard highly active antiretroviral therapy used to treat AIDS. It requires close compliance and can have unpleasant side effects including malaise, fatigue, diarrhea, headache, nausea and vomiting. A report from early 2013 revealed that a female baby born with the HIV virus displayed no sign of the virus two years after high doses of three antiretroviral drugs were administered within 30 hours of her birth. The findings of the case were presented at the 2013 Conference on Retroviruses and Opportunistic Infections in Atlanta, U.S. and the baby is from Mississippi, U.S. The baby—known as the "Mississippi baby"—was considered to be the first child to be "functionally cured" of HIV. However, HIV re-emerged in the child as of July 2014. Antiretroviral agents from three classes of drugs are available for the treatment of HIV infection. These agents include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Only antiretroviral agents that have been approved by FDA for treatment of HIV infection are discussed in these guidelines. Determining which agents and how many to use or when to alter a PEP regimen is largely empiric. Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, include recommendations for the use of three drugs (140); however, the applicability of these recommendations to PEP remains unknown. In HIV-infected patients, combination regimens have proved superior to monotherapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance (141,142). A combination of drugs with activity at different stages in the viral replication cycle (e.g., nucleoside analogues with a PI) theoretically could offer an additional preventive effect in PEP, particularly for occupational exposures that pose an increased risk of transmission. Although the use of a three-drug regimen might be justified for exposures that pose an increased risk of transmission, whether the potential added toxicity of a third drug is justified for lower-risk exposures is uncertain. Therefore, the recommendations at the end of this document provide guidance for two- and three-drug PEP regimens that are based on the level of risk for HIV transmission represented by the exposure. NRTI combinations that can be considered for PEP include ZDV and 3TC, 3TC and stavudine (d4T), and ddI and d4T. In previous PHS guidelines, a combination of ZDV and 3TC was considered the first choice for PEP regimens (3). Because ZDV and 3TC are available in a combination formulation (Combivir™, manufactured by Glaxo Wellcome, Inc., Research Triangle Park, NC), the use of this combination might be more convenient for HCP. However, recent data suggest that mutations associated with ZDV and 3TC resistance might be common in some areas (143). Thus, individual clinicians might prefer other NRTIs or combinations based on local knowledge and experience in treating HIV infection and disease. The addition of a third drug for PEP following high-risk exposures is based on demonstrated effectiveness in reducing viral burden in HIV-infected persons. Previously, indinavir (IDV) or nelfinavir (NFV) were recommended as first-choice agents for inclusion in an expanded PEP regimen (5). Since the publication of the 1998 PEP guidelines, efavirenz (EFV), an NNRTI; abacavir (ABC), a potent NRTI; and Kaletra™, a PI, have been approved by FDA. Although side effects might be common with the NNRTIs, EFV might be considered for expanded PEP regimens, especially when resistance to PIs in the source person's virus is known or suspected. ABC has been associated with dangerous hypersensitivity reactions but, with careful monitoring, may be considered as a third drug for PEP. Kaletra, a combination of lopinavir and ritonavir, is a potent HIV inhibitor that, with expert consultation, may be considered in an expanded PEP regimen. The Medical Care Criteria Committee now recommends tenofovir disoproxil fumarate + emtricitabine plus either raltegravir or dolutegravir as the preferred initial PEP regimen because of its excellent tolerability, proven potency in established HIV infection, and ease of administration. Zidovudine is no longer recommended in the preferred PEP regimen because it is believed to have no clear advantage in efficacy over tenofovir disoproxil fumarate while having significantly higher rates of treatment-limiting side effects. Toxicity and Drug Interactions of Antiretroviral Agents When administering PEP, an important goal is completion of a 4-week PEP regimen when PEP is indicated. Therefore, the toxicity profile of antiretroviral agents, including the frequency, severity, duration, and reversibility of side effects, is a relevant consideration. All of the antiretroviral agents have been associated with side effects (Table 2). However, studies of adverse events have been conducted primarily with persons who have advanced disease (and longer treatment courses) and who therefore might not reflect the experience in persons who are uninfected (144). Several primary side effects are associated with antiretroviral agents (Table 2). Side effects associated with many of the NRTIs are chiefly gastrointestinal (e.g., nausea or diarrhea); however, ddI has been associated with cases of fatal and nonfatal pancreatitis among HIV-infected patients treated for >4 weeks. The use of PIs has been associated with new onset diabetes mellitus, hyperglycemia, diabetic ketoacidosis, exacerbation of preexisting diabetes mellitus, and dyslipidemia (145--147). Nephrolithiasis has been associated with IDV use; however, the incidence of this potential complication might be limited by drinking at least 48 ounces (1.5 L) of fluid per 24-hour period (e.g., six 8- ounce glasses of water throughout the day) (148). NFV has been associated with the development of diarrhea; however, this side effect might respond to treatment with antimotility agents that can be prescribed for use, if necessary, at the time the drug is recommended for PEP. The NNRTIs have been associated with severe skin reactions, including life-threatening cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hepatotoxicity, including fatal hepatic necrosis, has occurred in patients treated with nevirapine (NVP); some episodes began during the first few weeks of therapy (FDA, unpublished data, 2000). EFV has been associated with central nervous system side effects, including dizziness, somnolence, insomnia, and abnormal dreaming. All of the approved antiretroviral agents might have potentially serious drug interactions when used with certain other drugs (Appendix C). Careful evaluation of concomitant medications used by an exposed person is required before PEP is prescribed, and close monitoring for toxicity is also needed. Further information about potential drug interactions can be found in the manufacturer's package insert. Toxicity Associated with PEP Information from the National Surveillance System for Health Care Workers (NaSH) and the HIV Postexposure Registry indicates that nearly 50% of HCP experience adverse symptoms (e.g., nausea, malaise, headache, anorexia, and headache) while taking PEP and that approximately 33% stop taking PEP because of adverse signs and symptoms (6,7,10,11). Some studies have demonstrated that side effects and discontinuation of PEP are more common among HCP taking three-drug combination regimens for PEP compared with HCP taking two-drug combination regimens (7,10). Although similar rates of side effects were observed among persons who took PEP after sexual or drug use exposures to HIV in the San Francisco Post-Exposure Prevention Project, 80% completed 4 weeks of therapy (149). Participants in the San Francisco Project were followed at 1, 2, 4, 26, and 52 weeks postexposure and received medication adherence counseling; most participants took only two drugs for PEP. Serious side effects, including nephrolithiasis, hepatitis, and pancytopenia have been reported with the use of combination drugs for PEP (6,7,150,151). One case of NVP-associated fulminant liver failure requiring liver transplantation and one case of hypersensitivity syndrome have been reported in HCP taking NVP for HIV PEP (152). Including these two cases, from March 1997 through September 2000, FDA received reports of 22 cases of serious adverse events related to NVP taken for PEP (153). These events included 12 cases of hepatotoxicity, 14 cases of skin reaction (including one documented and two possible cases of Stevens-Johnson syndrome), and one case of rhabdomyolysis; four cases involved both hepatotoxicty and skin reaction, and one case involved both rhabdomyolysis and skin reaction. Resistance to Antiretroviral Agents Known or suspected resistance of the source virus to antiretroviral agents, particularly to agents that might be included in a PEP regimen, is a concern for persons making decisions about PEP. Resistance to HIV infection occurs with all of the available antiretroviral agents, and cross-resistance within drug classes is frequent (154). Recent studies have demonstrated an emergence of drug-resistant HIV among source persons for occupational exposures (143,155). A study conducted at seven U.S. sites during 1998--1999 found that 16 (39%) of 41 source persons whose virus was sequenced had primary genetic mutations associated with resistance to RTIs, and 4 (10%) had primary mutations associated with resistance to PIs (143). In addition, occupational transmission of resistant HIV strains, despite PEP with combination drug regimens, has been reported (137,139). In one case, a hospital worker became infected after an HIV exposure despite a PEP regimen that included ddI, d4T, and NVP (139). The transmitted HIV contained two primary genetic mutations associated with resistance to NNRTIs (the source person was taking EFV at the time of the exposure). Despite recent studies and case reports, the relevance of exposure to a resistant virus is still not well understood. Empiric decisions about the presence of antiretroviral drug resistance are often difficult to make because patients generally take more than one antiretroviral agent. Resistance should be suspected in source persons when they are experiencing clinical progression of disease or a persistently increasing viral load, and/or decline in CD4 T-cell count, despite therapy or a lack of virologic response to therapy. However, resistance testing of the source virus at the time of an exposure is not practical because the results will not be available in time to influence the choice of the initial PEP regimen. Furthermore, in this situation, whether modification of the PEP regimen is necessary or will influence the outcome of an occupational exposure is unknown. No data exist to suggest that modification of a PEP regimen after receiving results from resistance testing (usually a minimum of 1--2 weeks) improves efficacy of PEP. Antiretroviral Drugs During Pregnancy Data are limited on the potential effects of antiretroviral drugs on the developing fetus or neonate (156). Carcinogenicity and/or mutagenicity is evident in several in vitro screening tests for ZDV and all other FDA-licensed NRTIs. The relevance of animal data to humans is unknown; however, because teratogenic effects were observed in primates at drug exposures similar to those representing human therapeutic exposure, the use of EFV should be avoided in pregnant women (140). IDV is associated with infrequent side effects in adults (i.e., hyperbilirubinemia and renal stones) that could be problematic for a newborn. Because the half-life of IDV in adults is short, these concerns might be relevant only if the drug is administered shortly before delivery. In a recent study in France of perinatal HIV transmission, two cases of progressive neurologic disease and death were reported in uninfected infants exposed to ZDV and 3TC (157). Laboratory studies of these children suggested mitochondrial dysfunction. In a careful review of deaths in children followed in U.S. perinatal HIV cohorts, no deaths attributable to mitochondrial disease have been found (158). Recent reports of fatal and nonfatal lactic acidosis in pregnant women treated throughout gestation with a combination of d4T and ddI have prompted warnings about use of these drugs during pregnancy (159). Although the case-patients were HIV-infected women taking the drugs for >4 weeks, pregnant women and their providers should be advised to consider d4T and ddI only when the benefits of their use outweigh the risks. =See also= =References= =Acknowledgements= This article was written by Roy Tan. Category:General articles